Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation-Deuteration of Heterobenzylic Methylenes

Article abstract of DOI:10.1021/acs.orglett.0c03108

We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.

Full text of DOI:10.1021/acs.orglett.0c03108

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Letter
Transition-Metal Free Chemoselective Hydroxylation and
Hydroxylation−Deuteration of Heterobenzylic Methylenes
Yonghai Liu,§ Yang Yu,§ Chengyu Sun, Yiwei Fu, Zhiguo Mang, Lei Shi, and Hao Li*
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ABSTRACT: We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols
avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes
to give hydroxylated products in 41−76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic
methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical
ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.
Scheme 1. Selective Hydroxylation of Heterobenzylic
he direct selective oxyfunctionalization of the benzylic
C(sp3)−H Bonds
3
TC(sp )−H bond to the formation of alcohols (lowest
oxidation state in contrast to corresponding ketones, aldehydes,
and carboxylic acids) is still challenging and limited.1 To date,
only a few examples of selective oxidation to hydroxylated
products employing enzymatic catalysis,2 bionic catalysis,3 and
core−shell catalysis4 have been reported. Very recently, Sekar5
and Ritter6 reported new strategies by the direct synthesis of
protected hydroxy groups such as the acetyl (Ac) or
methanesulfonyl (Ms) group, to minimize overoxidation to
the corresponding ketones (Scheme 1a,b). However, the direct
aerobic chemoselective oxidation of (hetero)benzylic C(sp3)−
H bonds to secondary alcohols remains a significant challenge.
There are two major reasons.5 (1) Most of the aerobic oxidation
procedures follow a radical pathway, whereby the readily formed
(hetero)benzylic radical intermediate immediately reacts with
molecular oxygen to form a peroxo intermediate, which is then
transformed into a carbonyl group (aldehyde/ketone) by the
elimination of H2O. In addition, the reduction of O2 to H2O is
highly exothermic, giving a thermodynamic driving force for
aerobic oxidation. (2) If some alcohols are obtained by cleavage
of the O−O bonds, they will be further oxidized to carbonyl
groups, because of the higher reactivity of alcohols compared to
that of the substrates in the presence of radical species.
Therefore, it is very necessary to develop a practical method-
ology to oxidize (hetero)benzylic methylenes to secondary
alcohols directly with ambient air as the terminal oxidant.7
Aryl(pyridin-2-yl)methanols have been widely used for the
synthesis of active pharmaceutical ingredients (APIs) such as
bepotastine, carbinoxamine, and doxylamine, which are effective
Received: September 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03108
© XXXX American Chemical Society
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A

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a
Table 1. Optimization of Reaction Conditions
b
yield (%)
3a
15
entry
base
t (min)
solvent
2a
4a
c
1
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
LiOBu-t
NaOBu-t
KOH
4
15
30
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
toluene
MeCN
tetramethylene sulfoxide
DMSO
DMSO
DMSO
DMSO
DMSO
59
45
25
71
72
42
7
31
40
trace
trace
trace
trace
86
−
27
14
trace
15
36
−
−
d
2
9
e
3
13
10
8
37
78
−
−
−
−
trace
4
5
f
3
6
7
30
30
60
60
60
4
30
30
60
60
60
g
trace
trace
no reaction
18
41
trace
24
42
8
9
10
11
12
13
14
15
16
7
trace
−
DBU
DABCO
no reaction
no reaction
−
a
Unless specified, to a solution of a base (1.5 mmol) in 2 mL of anhydrous DMSO was added dropwise 2-benzylpyridine 1a (0.5 mmol) in 1 mL of
anhydrous DMSO (0.5 mol/L) in 1 min, and the reaction mixture under ambient air was stirred at 30 °C until 1a was consumed, as monitored by
b
c
d
e
f
g
TLC. Isolated yield. With 2 equiv of KOBu-t. With 1 equiv of KOBu-t. With 0.5 equiv of KOBu-t. With 4 equiv of KOBu-t. The reaction was
carried out at 60 °C.
antagonists of the histamine 1 (H1) receptor in the treatment of
allergic rhinitis, chronic urticaria, and skin diseases.8
yield (entry 6). The reaction at 60 °C gave only product 3a in
78% yield (entry 7). In addition, solvent screening revealed that
only trace amounts of products were obtained in DMF, toluene,
or CH3CN, whereas tetramethylene sulfoxide afforded 2a in a
lower yield (entry 11, 41% yield). These results revealed that the
sulfoxide moiety was important and DMSO was the most
suitable solvent for this reaction. In addition, LiOBu-t, NaOBu-t,
KOH, and organic bases such as 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO)
were shown to be less efficient (entries 12−16, respectively).
After optimizing the reaction conditions, we then examined
the process using a variety of substrates. As shown in Scheme 2,
all of the tested substrates produced the hydroxylated products 2
within 2−9 min in moderate to good isolated yields with minor
byproducts 3. The reaction could well tolerate electron-
withdrawing groups (EWGs) such as F and Cl (2b and 2c,
58% and 60% yields, respectively), an electron-donating group
(EDG) (Me, 2d, 62% yield), and an electron-neutral group
(vinyl group, 2e, 53% yield) on the para position of the benzene
rings. A meta-Me-substituted benzene ring also provided the
desired product 2f in 61% yield. Interestingly, more sterical
substrates, involving o-Me and o-Br substitution of the benzene
ring, afforded the corresponding alcohols in good yields (71%
for 2g and 68% for 2h). Other aromatic substrates, including 2-
naphthalene, 1-naphthalene, and thiophene, also resulted in
smooth reactions, affording 2i−2k, respectively, in good yields.
In addition, the substrates with a pyridine ring bearing -Me,
-OMe, and -Cl groups were also shown to be compatible with
this process (2l−2o). Similarly, the pyridines bearing a C-3
furnished the corresponding alcohols with higher yields (2l−
2n). Besides 2-benzylpyridine derivatives, 4-benzylpyridine
substrates also provided the desired products (2p−2s) in
moderate to good yields. Furthermore, other azaarenes,
Traditionally, aryl(pyridin-2-yl)methanols have been synthe-
sized via a two-step process: oxidation of benzylpyridines to
benzoylpyridines followed by monohydrogenation.9 It is highly
desirable to develop direct conversion of heterobenzylic
C(sp3)−H to corresponding alcohols. Herein, to continue our
study of functionalization of azaarenes10 and aerobic C−O
formation reactions,11 we report our studies of a chemoselective
transition-metal free aerobic hydroxyfunctionalization of
heterobenzylic C(sp3)−H bonds to synthesize secondary
alcohols by using air as the sole oxidant with high chemo-
selectivities and moderate to excellent yields. Moreover,
deuterated secondary alcohols can be obtained via “one-pot”
site-specific hydroxylation−deuteration of heterobenzylic meth-
ylenes by using DMSO-d6 as the solvent (Scheme 1c).
We commenced our studies by investigating the model
reaction of 2-benzylpyridine 1a (0.5 mmol in 1 mL of DMSO) in
a solution of a base (1.0 mmol) in DMSO (2 mL) (Table 1).
According to the independent reports of Maes12 and Gao,13
a
small amount of phenyl(pyridin-2-yl)methanol 2a was formed
as only the byproduct in the oxidation of 2-benzylpyridine to
form phenyl(pyridin-2-yl)methanone. In contrast, in the
presence of 2 equiv of KOBu-t for 4 min at 30 °C, 2a was
obtained in 59% yield with 15% DMSO-linked byproduct 3a
and 7% ketone byproduct 4a (Table 1, entry 1). Encouraged by
this result, we then varied the reaction conditions to optimize
the yield of 2a. Decreasing the amount of KOBu-t led to the
increasing yields of byproducts (entries 2 and 3). Increasing the
amount of KOBu-t favored the formation of 2a with <10% 3a
and a trace amount of 4a (entries 4 and 5, respectively), and 3
equiv was found to be necessary (entry 4, 71% yield). Moreover,
the results showed that a prolonged reaction time led to a lower
B
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Scheme 2. Hydroxylation Reactions of Heterobenzylic
Scheme 3. Difunctionalization of Heterobenzylic C(sp3)−H
a
a
C(sp3)−H Bonds
Bonds
a
Reaction conditions: To a solution of KOBu-t (0.9 mmol) in 1.5 mL
a
of anhydrous DMSO-d6 was added dropwise 1 (0.3 mmol) in 0.5 mL
of anhydrous DMSO-d6 (0.6 mol/L) in 1 min, and the mixture was
stirred at 30 °C under ambient air. Isolated yield.
Reaction conditions: To a solution of KOBu-t (1.5 mmol) in 2 mL
of anhydrous DMSO was added dropwise substrate 1 (0.5 mmol) in 1
mL of anhydrous DMSO (0.5 mol/L) in 1 min, and the solution was
b
stirred at 30 °C under ambient air. Isolated yield of 2. The yield of 3
1
trisubstituted methanols17 as potential API intermediates.
Indeed, when aryl- or alkyl-substituted benzylpyridines 5 were
submitted to the optimized reaction, tertiary alcohols 6 were
successfully obtained in satisfactory yields (Scheme 4). For
(<10%) was based on the H NMR analysis of the crude mixture.
c
Isolated yield of 3. The characterization data are reported in the
d
Supporting Information. The isolated yield of 4i (11%) is reported
in the Supporting Information.
Scheme 4. Hydroxylation Reactions of Heterobenzylic
including isoquinoline, quinoline, pyrazine, and pyrimidine,
were also tested as substrates for this hydroxylation reaction.
Gratifyingly, the expected products were formed in moderate
yields (2t−2w). Moreover, the LC-MS study for character-
ization of the corresponding byproducts was performed by
employing 1t as the substrate. The mass peaks for 2t and 3t
could be detected (see Figure S11). It is noteworthy that a new
tridentate ligand based on 2,2′-bipyridine was synthesized by
this novel methodology in 65% yield (2x).
a
C(sp3)−H Bonds
The synthesis of α-deuterated alcohols is an important
research area in organic chemistry due to their significance in
pharmaceuticals.14 Traditional methods for the synthesis of α-
deuterated alcohols include the reduction of carbonyl
compounds with deuterated reducing agents such as LiAlD4
and NaBD4,15 or transition-metal-catalyzed H/D exchange.16
We now report that a practical “one-pot” difunctionalization
(hydroxylation−deuteration) of 2-benzylpyridine derivatives
gives α-deuterated aryl(pyridin-2-yl)methanol 2′ by using
DMSO-d6 as the solvent, which has the advantages of being
inexpensive, readily available, and highly safe (for optimization
of reaction conditions, see Table S1). Various benzylpyridine
derivatives 1 afforded the desired deuterated aryl(pyridinyl)-
methanols 2′ with 93−98% benzylic deuteration after aqueous
workup and without any sacrifice of yield (Scheme 3). Besides,
the reactions also gave the deuterated DMSO-linked byproducts
3′ similarly (10% isolated yield for 3a′).
a
Reaction conditions: To a solution of KOBu-t (1.5 mmol) in 2 mL
of anhydrous DMSO was added dropwise 5 (0.5 mmol) in 1 mL of
anhydrous DMSO (0.5 mol/L), and the mixture was stirred for 0.5−2
b
h at 30 °C under ambient air. Isolated yield. The reaction was carried
c
out under O2 for 20 h. The reaction mixture was stirred for 10 h
under ambient air.
On the contrary, Sekar8c and Maes8d have independently
reported iron-catalyzed C−H hydroxylation to form N-hetero-
cycle-containing triarylmethanols or (alkyl)(aryl)-
azinylmethanols from the corresponding substrates. However,
these reactions normally require high temperatures or long
reaction times. To overcome these difficulties, we now report an
extension of our KOBu-t-promoted hydroxylation of hetero-
benzylic C(sp3)−H bonds for the synthesis of N-heterocyclic
example, 2-benzhydrylpyridine 5a led to the desired product 6a
in an excellent yield. Furthermore, both EWGs and EDGs on the
derivatives were formed in excellent yields (89−91%). It is
important to note that the reaction of 2-(9H-fluoren-9-
yl)pyridine 5o also proceeded smoothly. Moreover, a range of
alkyl-substituted tertiary alcohols 6, such as Me (6p, 86%), Bu
(6q, 84%), cyclohexyl (6r, 92%), and Bn (6s, 88%), were also
obtained in high yields. Substrates containing diverse function-
C
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alities such as a terminal olefin or an epoxide group were also
investigated, to afford 6t and 6u successfully in 91% and 65%
yields, respectively.
a resonance characteristic of an organic radical (see Figure
S10b). Moreover, when 2 equiv of 5,5-dimethyl-1-pyrroline N-
oxide (DMPO) was added, the superoxide free radical signal
appeared (see Figure S10c). In addition, (methylsulfonyl)-
methane was detected in the GC-MS analysis. This result reveals
that DMSO is the reductant, being oxidized in accepting one
oxygen atom in the reaction.
To test the practicality of this methodology, a gram-scale
reaction using substrate 5p was carried out (see page S38 of the
Supporting Information). The product 6p was obtained with a
comparable yield (1.00 g, 84% yield). By employing this novel
strategy, API carbinoxamine was synthesized from 2-(4-
chlorobenzyl)pyridine in two steps by selective hydroxylation
and O-alkylation in 48% overall yield. Similarly, another API,
doxylamine, was obtained from 2-(1-phenylethyl)pyridine in a
65% overall yield (Scheme 5).
On the basis of the results presented above, a possible reaction
mechanism is proposed in Scheme 6. Initially, intermediate I
Scheme 6. Proposed Mechanism of Selective Hydroxylation
Scheme 5. Application for the Synthesis of APIs
Carbinoxamine and Doxylamine
To understand the mechanism of this chemoselective
hydroxylation reaction, we performed several control experi-
ments and in situ spectroscopic investigations. First, the reaction
of 1a was carried out under a N2 atmosphere. Not surprisingly,
hydroxylated product 2a was not obtained and most of the 1a
was recovered, indicating the necessity of molecular oxygen for
this reaction. Upon addition of 5 equiv of 2,2,6,6-tetramethylpi-
peridinooxy (TEMPO) to the reaction mixture under a N2
atmosphere, the corresponding TEMPO coupling product 7a
was isolated in 85% yield (see Figure S6). This implies that the
reaction proceeds via the heterobenzylic radical intermediate.
Moreover, it was gratifying to find that the radical species could
be trapped by ethene-1,1-diyldibenzene to give radical addition
product 8a (see Figure S7). To capture the reaction
intermediate, the deuteration experiment was carried out by
using 1 equiv of KOBu-t as a base and DMSO-d6 as the solvent.
After 3.5 min, α-deuterated aryl(pyridin-2-yl)methanol 2a′ and
dideuterated 2-benzylpyridine 1a′ were separated in 47% and
37% yields, respectively (see Figure S8). When diphenyl-
methane was tested in this reaction, no desired product was
observed and most of the diphenylmethane was recycled (88%
recycled with 44.5% deuterated) under the same condition (see
Figure S8). This indicated that a N-containing heterocycle was
necessary for this reaction. Furthermore, under the standard
reaction condition, 1a′ could react smoothly to give 2a′.
Additionally, deuterated 2a′ could not be formed by employing
2a as the substrate (see Figure S8). These results indicated that
the deuteration of substrates was much faster than the
hydroxylation process. Under the standard condition, byproduct
3a could be obtained in 85% yield from ketone 4a in 5 min (see
Figure S9). Furthermore, EPR and GC-MS investigations were
also performed to better understand the reaction mechanism
with 5p as the substrate. When KOBu-t and DMSO were tested,
no EPR signal was observed (see Figure S10a). However, the
EPR spectrum of a mixture of 5p, KOBu-t, and DMSO displayed
facilitates formation of an enamine tautomer that is more
susceptible to aerobic oxygenation.18 Then I is induced by a
DMSO free radical in the presence of KOBu-t to form radical II
(detected by EPR).19 Radical II reacts with molecular oxygen to
give intermediate III (detected by EPR), which abstracts a
hydrogen atom from 1a to afford radical II and hydroperoxide
IV.20 Finally, 2a is formed by reduction of IV with DMSO
instead of the typical dehydration to give ketone 4a. DMSO is
oxidized to dimethyl sulfone [detected by GC-MS (see Figure
S12)].4,21 Ketone 4a is generated from 2a via dioxygen
oxidation. Another byproduct 3a is formed by nucleophilic
addition reaction between ketone 4a and DMSO anion. The
formation of 2a from 1a and the formation of 3a from 4a are
rapid reactions, and the formation of ketone 4a from alcohol 2a
is slower.
In summary, using a KOBu-t/DMSO/air system, we have
developed the first example of a transition-metal free direct
hydroxylation of benzylpyridine derivatives to their correspond-
ing secondary alcohols, with high chemoselectivity, in moderate
to good yields. In addition, by employing DMSO-d6 as the
solvent, site-selective hydroxylation−deuteration of heteroben-
zylic methylenes has been demonstrated to be a very efficient
difunctionalization strategy to afford α-deuterated secondary
alcohols with >93% deuteration. Mechanistic studies indicate
that the hydroxylation reaction proceeds via a radical pathway.
By employing this novel strategy, two APIs, carbinoxamine and
doxylamine, were synthesized in a practical two-step sequence in
moderate yields.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03108.
Experimental details and spectroscopic data (PDF)
D
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Chem. Soc. 2013, 135, 17282. (c) Oohora, K.; Meichin, H.; Kihira, Y.;
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(4) Liu, M.; Shi, S.; Zhao, L.; Wang, M.; Zhu, G.; Zheng, X.; Gao, J.;
Xu, J. ACS Catal. 2018, 8, 683.
AUTHOR INFORMATION
Corresponding Author
■
Hao Li − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China; orcid.org/0000-0002-8978-
0247; Email: hli77@ecust.edu.cn
(5) Guha, S.; Sekar, G. Chem. - Eur. J. 2018, 24, 14171.
̈
(6) Tanwar, L.; Borgel, J.; Ritter, T. J. Am. Chem. Soc. 2019, 141,
17983.
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Authors
Yonghai Liu − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Yang Yu − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Chengyu Sun − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Yiwei Fu − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
̀
(d) Sterckx, H.; Sambiagio, C.; Lemiere, F.; Tehrani, K. A.; Maes, B. U.
W. Synlett 2017, 28, 1564.
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(b) Ren, L.; Gao, S. Youji Huaxue 2017, 37, 1338.
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Zhiguo Mang − State Key Laboratory of Bioreactor Engineering,
Shanghai Key Laboratory of New Drug Design, and School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Lei Shi − Corporate R&D Division, Firmenich Aromatics (China)
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(16) (a) Rosales, A.; Mun
Castaneda, M. A.; Padial, N. M.; Gansauer, A.; Rodríguez-García, I.;
̃
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03108
Oltra, J. E. J. Org. Chem. 2014, 79, 7672. (b) Maegawa, T.; Fujiwara, Y.;
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Author Contributions
§Y.L. and Y.Y. contributed equally to this work.
(17) For selected examples of transition-metal free synthesis of tertiary
alcohols, see: (a) Liang, Y.; Jiao, N. Angew. Chem., Int. Ed. 2014, 53, 548.
(b) Chaudhari, M. B.; Sutar, Y.; Malpathak, S.; Hazra, A.;
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Notes
The authors declare no competing financial interest.
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(19) DMSO radical was formed under a KOBu-t/DMSO/air system:
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21572054), the program for Professor of
Special Appointment (Eastern Scholar) at Shanghai Institutions
of Higher Learning, the Fundamental Research Funds for the
Central Universities, and the China 111 Project (Grant
B07023).
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